Effects of temporal IFNγ exposure on macrophage phenotype and secretory profile: exploring GMP-Compliant production of a novel subtype of regulatory macrophages (MregIFNγ0) for potential cell therapeutic applications.

BACKGROUND: Macrophages are involved in tissue homeostasis, angiogenesis and immunomodulation. Proangiogenic and anti-inflammatory macrophages (regulatory macrophages, Mreg) can be differentiated in-vitro from CD14+ monocytes by using a defined cell culture medium and a stimulus of IFNγ. AIM OF THE STUDY: To scrutinize the potential impact of temporal IFNγ exposure on macrophage differentiation as such exposure may lead to the emergence of a distinct and novel macrophage subtype. METHODS: Differentiation of human CD14+ monocytes to Mreg was performed using a GMP compliant protocol and administration of IFNγ on day 6. Monocytes from the same donor were in parallel differentiated to MregIFNγ0 using the identical protocol but with administration of IFNγ on day 0. Cell characterization was performed using brightfield microscopy, automated and metabolic cell analysis, transmission electron microscopy, flow cytometry, qPCR and secretome profiling. RESULTS: Mreg and MregIFNγ0 showed no differences in cell size and volume. However, phenotypically MregIFNγ0 exhibited fewer intracellular vesicles/vacuoles but larger pseudopodia-like extensions. MregIFNγ0 revealed reduced expression of IDO and PD-L1 (P < 0.01 for both). They were positive for CD80, CD14, CD16 and CD38 (P < 0.0001vs. Mreg for all), while the majority of MregIFNγ0 did not express CD206, CD56, and CD103 on their cell surface (P < 0.01 vs. Mreg for all). In terms of their secretomes, MregIFNγ0 differed significantly from Mreg. MregIFNγ0 media exhibited reduced levels of ENA-78, Osteopontin and Serpin E1, while the amounts of MIG (CXCL9) and IP10 were increased. CONCLUSION: Exposing CD14+ monocytes to an alternatively timed IFNγ stimulation results in a novel macrophage subtype which possess additional M1-like features (MregIFNγ0). MregIFNγ0 may therefore have the potential to serve as cellular therapeutics for clinical applications beyond those covered by M2-like Mreg, including immunomodulation and tumor treatment.

Evaluation of the MMI Symani® robotic microsurgical system for coronary-bypass anastomoses in a cadaveric porcine model.

The MMI Symani® is a recently approved robotic microsurgical system for surgical procedures in adults. The system enables the surgeon to create microanastomoses. Clinical applications so far include lymphatic vessels surgery and the creation of special flap plastics. The use of the system in coronary arteries has not yet been assessed. The aim of this preclinical study was to evaluate the applicability of the Symani® surgical system in the creation of coronary anastomoses a cadaveric porcine model. A total of 12 anastomoses were performed by three senior cardiovascular surgeons on the left main coronary artery of three porcine hearts. Artificial bypasses (diameter 1 mm) were performed to the left main trunk. The anastomoses were performed with the Symani® surgical system. Evaluation included procedure times and anastomosis leakage. All anastomoses could be successfully performed. The procedure time decreased due to the learning curve between the first anastomosis 47:28 ± 5:30 min and the last anastomosis 22:37 ± 3:25 min. The final evaluation of the anastomoses showed excellent results with low leakage. The quality of the anastomosis also improved in relation to the increasing learning curve. The Symani® surgical system could be used to create coronary anastomoses in an acceptable time frame and without technical failures. Hence, the system appears feasible for conventional coronary surgery. Further studies in animal models are mandatory prior to clinical application.

Trans-Brachial TAVI in a Patient with Aortic Isthmus Stenosis: A Case Report.

BACKGROUND: TAVI indications expand not only to low-risk patients but also to patients with a more complex anatomy and comorbidities. Transfemoral retrograde access is recognized as the first preferred approach according to the current guidelines. However, this approach is not suitable in up to 10-15% of patients, for whom an alternative non-femoral access route is required. CASE PRESENTATION: An 83-year-old male patient with known aortic isthmus stenosis presented with severe symptomatic aortic stenosis. Computed tomography revealed a subtotal isthmus stenosis, directly after left subclavian artery origin, with many collaterals extending toward the axillary and subclavian arteries. Duplex ultrasound verified the proximal diameter of the left brachial artery to be 5.5 mm. A successful surgical cutdown trans-brachial TAVI with an Evolut prosthetic valve with a size of 29 mm was performed. On the fourth postoperative day, the patient was discharged, and the three-month follow-up was uneventful. CONCLUSION: In patients with aortic isthmus stenosis, the brachial artery could be a feasible alternative, as a less invasive access site, which can be determined after careful assessment of the vessel diameter. More data are required to evaluate the safety and efficacy of this access route and to achieve more technical improvements to increase operator familiarity with it.

Functional bony entrapment of the dorsalis pedis artery caused by cranial subluxation in the talonavicular joint.

A 66-year-old female presented in the emergency department with Blue-Toe-Syndrome (BTS) and signs of osteitis of her left big toe. Imaging workup of the peripheral vasculature showed no findings. Upon invasive angiography, severe focal stenosis of the dorsalis pedis artery (DPA) could be seen at the talonavicular joint. Complete regression of the stenosis was inducible by dorsal extension in the ankle joint. Further imaging revealed an underlying subluxation of the talonavicular joint as cause of the arterial compression. Entrapment of the DPA is a rare condition and most often described in relation to connective tissue bands or variant muscular tendons (McCabe et al. 70:213-8, 2021; Weichman et al. 24:113, 2010; Smith et al.58:212-4, 2013; Griffin et al. 20:325-8; 2012). In the presented case, bony compression of the PDA due to cranial subluxation of the talus was seen as the cause of BTS and osteitis of the phalanx of the first toe.

Large extracellular vesicles derived from human regulatory macrophages (L-EVMreg) attenuate CD3/CD28-induced T-cell activation in vitro.

Macrophages belong to the innate immune system, and we have recently shown that in vitro differentiated human regulatory macrophages (Mreg) release large extracellular vesicles (L-EVMreg) with an average size of 7.5 µm which regulate wound healing and angiogenesis in vitro. The aim of this study was to investigate whether L-EVMreg also affect the CD3/CD28-mediated activation of T-cells. Mreg were differentiated using blood monocytes and L-EVMreg were isolated from culture supernatants by differential centrifugation. Activation of human T-cells was induced by CD3/CD28-coated beads in the absence or presence of Mreg or different concentrations of L-EVMreg. Inhibition of T-cell activation was quantified by flow cytometry and antibodies directed against the T-cell marker granzyme B. Phosphatidylserine (PS) exposure on the surface of Mreg and L-EVMreg was analyzed by fluorescence microscopy. Incubation of human lymphocytes with CD3/CD28 beads resulted in an increase of cell size, cell granularity, and number of granzyme B-positive cells (P < 0.05) which is indicative of T-cell activation. The presence of Mreg (0.5 × 106 Mreg/ml) led to a reduction of T-cell activation (number of granzyme B-positive cells; P < 0.001), and a similar but less pronounced effect was also observed when incubating activated T-cells with L-EVMreg (P < 0.05 for 3.2 × 106 L-EVMreg/ml). A differential analysis of the effects of Mreg and L-EVMreg on CD4+ and CD8+ T-cells showed an inhibition of CD4+ T-cells by Mreg (P < 0.01) and L-EVMreg (P < 0.05 for 1.6 × 106 L-EVMreg/ml; P < 0.01 for 3.2 × 106 L-EVMreg/ml). A moderate inhibition of CD8+ T-cells was observed by Mreg (P < 0.05) and by L-EVMreg (P < 0.01 for 1.6 × 106 L-EVMreg/ml and 3.2 × 106 L-EVMreg/ml). PS was restricted to confined regions of the Mreg surface, while L-EVMreg showed strong signals for PS in the exoplasmic leaflet. L-EVMreg attenuate CD3/CD28-mediated activation of CD4+ and CD8+ T-cells. L-EVMreg may have clinical relevance, particularly in the treatment of diseases associated with increased T-cell activity. KEY MESSAGES: Mreg release large extracellular vesicles (L-EVMreg) with an average size of 7.5 µm L-EVMreg exhibit phosphatidylserine positivity L-EVMreg suppress CD4+ and CD8+ T-cells L-EVMreg hold clinical potential in T-cell-related diseases.

Characterization of large extracellular vesicles (L-EV) derived from human regulatory macrophages (Mreg): novel mediators in wound healing and angiogenesis?

BACKGROUND: Large extracellular vesicles (L-EV) with a diameter between 1 and 10 µm are released by various cell types. L-EV contain and transport active molecules which are crucially involved in cell to cell communication. We have shown that secretory products of human regulatory macrophages (Mreg) bear pro-angiogenic potential in-vitro and our recent findings show that Mreg cultures also contain numerous large vesicular structures similar to L-EV with so far unknown characteristics and function. AIM OF THIS STUDY: To characterize the nature of Mreg-derived L-EV (L-EVMreg) and to gain insights into their role in wound healing and angiogenesis. METHODS: Mreg were differentiated using blood monocytes from healthy donors (N = 9) and L-EVMreg were isolated from culture supernatants by differential centrifugation. Characterization of L-EVMreg was performed by cell/vesicle analysis, brightfield/transmission electron microscopy (TEM), flow cytometry and proteome profiling arrays. The impact of L-EVMreg on wound healing and angiogenesis was evaluated by means of scratch and in-vitro tube formation assays. RESULTS: Mreg and L-EVMreg show an average diameter of 13.73 ± 1.33 µm (volume: 1.45 ± 0.44 pl) and 7.47 ± 0.75 µm (volume: 0.22 ± 0.06 pl) respectively. Flow cytometry analyses revealed similarities between Mreg and L-EVMreg regarding their surface marker composition. However, compared to Mreg fewer L-EVMreg were positive for CD31 (P < 0.01), CD206 (P < 0.05), CD103 (P < 0.01) and CD45 (P < 0.05). Proteome profiling suggested that L-EVMreg contain abundant amounts of pro-angiogenic proteins (i.e. interleukin-8, platelet factor 4 and serpin E1). From a functional point of view L-EVMreg positively influenced in-vitro wound healing (P < 0.05) and several pro-angiogenic parameters in tube formation assays (all segment associated parameters, P < 0.05; number of meshes, P < 0.05). CONCLUSION: L-EVMreg with regenerative and pro-angiogenic potential can be reproducibly isolated from in-vitro cultured human regulatory macrophages. We propose that L-EVMreg could represent a putative therapeutic option for the treatment of chronic wounds and ischemia-associated diseases.

Robot-Assisted Surgery of an Iliac Artery Aneurysm: A Case Report.

Robot-assisted surgery has not yet been able to establish itself for vascular surgery. However, the preconditions for robot-assisted vascular interventions have changed fundamentally over the past years because of technological advances and extensive experience in other surgical disciplines. Hence, we describe a robot-assisted repair of an iliac artery aneurysm using a late-generation robotic platform. A 63-year-old male patient was diagnosed with an asymptomatic 30 mm aneurysm of the right common iliac artery. The operation was performed with the Da Vinci Xi system (Intuitive Surgical, Inc., Sunnyvale, CA, USA) using a direct transperitoneal approach to repair the aneurysm by interposition of a Dacron vascular prothesis. The total operating duration was 304 minutes without perioperative need for blood transfusion. The patient was discharged on the eighth postoperative day after an uneventful postoperative course. The case presented shows that robot-assisted surgery in the iliac axis can be performed safely with reasonable operating times.

Repetitive application of remote ischemic conditioning (RIC) in patients with peripheral arterial occlusive disease (PAOD) as a non-invasive treatment option: study protocol for a randomised controlled clinical trial.

BACKGROUND: The best medical treatment (BMT) for most patients with early stage of peripheral arterial occlusive disease (PAOD) is often limited to gait training and pharmacological therapy besides endovascular surgery. The application of remote ischemic conditioning (RIC) has been described as a promising experimental strategy for the improvement of therapeutic outcome in cardiovascular disease but has not proven beneficial effects in clinical practice and treatment of PAOD yet. METHODS: Here we describe a prospective, randomized trial for the evaluation of possible effects of repeated application of RIC in patients with PAOD. This monocentric study will enrol 200 participants distributed to an intervention group receiving RIC + BMT and a control group only receiving BMT for four weeks. Patients are at least 18 years of age and have diagnosed PAOD Fontaine stage II b. Pain-free and total walking distance will be measured via treadmill test (primary endpoints). In addition, ankle-brachial index (ABI) and quality of life (QoL) will be assessed using the SF-36 and VascuQoL-6 questionnaire. Moreover, evaluation of markers for atherosclerosis, angiogenic profiling and mononuclear cell characterization will be performed using biochemical assays, proteome profiling arrays and flow cytometry (secondary endpoints). DISCUSSION: Our prospective, randomized monocentric trial is the first of its kind to analyse the effects of chronic and repetitive treatment with RIC in patients with PAOD and might provide important novel information on the molecular mechanisms associated with RIC in PAOD patients. TRIAL REGISTRATION: Prospectively registered in the German Clinical Trials Register (Deutsche Register Klinischer Studien) Registration number: DRKS00025735; Date of registration: 01.07.2021.

Percutaneous Thrombectomy in Patients with Occlusions of the Aortoiliac Segment: A Case Series.

OBJECTIVE: Thrombectomy of the aortoiliac segment remains a challenge for surgical and endovascular revision. This study aimed to evaluate the concept of percutaneous thrombectomy in patients with aortoiliac segment occlusions. MATERIALS & METHODS: Eighteen patients with aortoiliac occlusion who underwent percutaneous thrombectomy were retrospectively identified using the local picture archive and divided into the stent-graft (N = 10) and native vessels (N = 8) groups. The procedure was performed by placing a 12-24 French sheath adjacent to the distal end of the occluded vessel segment. The occlusion was passed with a balloon catheter which was retracted after inflation, to deliver the thrombus into the sheath. Technical success (reperfusion of the vessel and no residual thrombus/stenosis < 30%), complications and primary arterial patency were assessed. Follow-up included computed tomography angiography and evaluation of the clinical situation via telephone. RESULTS: Technical success was achieved in 38% (7/18) of patients after percutaneous thrombectomy alone and in 100% after additional procedures. The most common complication was peripheral embolism (44%, 8/18), which was treated successfully in all cases and was linked to a mismatch between the sheath and target vessel of ≥ 1 mm (P < .01). There were no significant differences in the incidence of complications between the two groups. Primary patency was 72% (13/18) with no significant difference between groups (P = .94). Follow-up CT scans were available for 13/18 patients (72%), with a mean follow-up time of 270 ± 146 days. All patients were contacted via phone (follow-up time, 653 ± 264 days). CONCLUSION: Percutaneous thrombectomy appears to be effective for revascularization of the aortoiliac segment, both in stent-grafts and in native vessels. The most common complication is peripheral embolism; however, the risk may be reduced by choosing an adequate sheath size.

Progressive cervical tumour in an HIV-patient: giant pseudoaneurysm of the carotid artery: a case report.

Background: Aneurysms of the extracranial carotid artery are a rare entity and correspond to <1% of all arterial aneurysms. Case summary: A 58-year-old male with known human immunodeficiency virus (HIV) infection presented in the emergency department with a massive cervical tumour on the right side of the neck and a severe occipital pain. Contrast computed tomography demonstrated a pseudoaneurysm of the proximal right internal carotid artery (ICA). Open surgery of the ICA was performed with reconstruction of the posterior vessel wall, embolectomy of the ICA, and anterior pericardial patch reconstruction. After an uneventful postoperative course, the patient was readmitted 4 weeks later with a right retrobulbous haematoma caused by a carotid cavernous fistula. Therefore a coil-embolization of the fistula and finally of the distal right carotid artery was performed. Discussion: In patients with a proven HIV infection, the occurrence of a vasculopathy in the extra- or intracranial carotid artery is significantly increased and the second most common site after the lower extremities. In patients with progredient neck swelling it should be considered in the differential. Surgical therapy is the preferred treatment strategy in the extracranial aneurysm type, especially in this patient collective.

Robotic-assisted abdominal aortic surgery: evidence and techniques.

In various disciplines, robotic-assisted surgery is a well-proven routine procedure, but have never been established in vascular surgery so far. This review summarizes the results to date of robotic-assisted abdominal aortic surgery (RAAS) in the treatment of aorto-iliac occlusive disease (AIOD) and abdominal aortic aneurysm (AAA). Web-based literature search of robotic-assisted surgical procedures on the abdominal aorta and iliac arteries between 1990 and 2020 including the Cochrane Library, OVID Medline, Embase, and PubMed medical databases. All studies conducting Robotic-assisted surgery were included in the quantitative analysis regarding operative and cross-clamping times, conversion rates, mortality and morbidity within the first 30 days, and in-hospital stay. Case reports and case studies (< 5 patients) were not included. Twenty-four studies were deemed thematically eligible for inclusion; after exclusion of duplicate publications, nine met the inclusion criteria for further analysis. A total of 850 patients who had either abdominal aortic aneurysm or aorto-iliac occlusive disease underwent RAAS. One study of abdominal aortic aneurysm, three of aorto-iliac occlusive disease, and five studies of both disease entities were analyzed quantitatively. For AAA, conversion rates ranged from 13.1 to 20% and perioperative mortality ranged from 0 to 1.6% with in-hospital stay of 7 days. For aorto-iliac occlusive disease, conversion rates ranged from 0 to 20%, and perioperative mortality ranged from 0 to 3.6% with in-hospital stay of 5-8 days. RAAS has been shown to be technically feasible with acceptable short-term outcomes and questionable benefits in terms of in-hospital stay and complication rates. RAAS is currently considered only an outsider procedure. Randomized-controlled trials are indispensable for regular use in vascular surgery as well as a clear approval situation for the vascular sector.

Repair of the descending thoracic aorta using minimally invasive endoscopic Robot-assisted surgery: a feasibility study with the DaVinci XI system in a cadaver model.

Development of minimally invasive techniques has led to the clinical routine application of Robot-assisted surgery. Here, we demonstrate for the first time Robotic-assisted surgery (DaVinci XI) of the descending thoracic aorta in a Thiel cadaver model and discuss its potential value in the endovascular era.

Experimental Evaluation of the Effectiveness of Aspiration-Based Techniques to Treat Different Types of Acute Thromboembolic Occlusions in the Femoropopliteal Vascular System Using an In Vitro Flow Model.

PURPOSE: In this in vitro study, the effectiveness and safety of four aspiration-based techniques for thrombectomy are evaluated for three types of thrombi in a flow model simulating the femoropopliteal segment. MATERIAL AND METHODS: Red, white, and mixed thrombi were produced in a standardized manner and used to simulate occlusion of a superficial femoral artery using a pulsatile flow model. Four techniques were compared: aspiration alone, aspiration + stent retriever, exposing thrombus to laser by an excimer laser system and a laser catheter + aspiration, and aspiration + mechanical fragmentation by a separator. Rate of first-pass recanalization, embolic events, and number of embolized fragments > 1 mm were compared. RESULTS: Aspiration alone, stent retriever, laser, and separator differed in rates of first-pass recanalization (53.3%; 86.6%; 20%; and 100%) and embolic events (40%; 93.3%; 73.3%; and 60%). Number of embolized fragments was lowest with aspiration and higher with separator, laser, and stent retriever. Rates of first-pass-recanalization (75%; 75%; and 45%) and embolic events (65%; 60%; and 75%) differed for red, white, and mixed thrombi. The mixed thrombus caused the highest number of embolized fragments, which was particularly high using the stent retriever. CONCLUSION: Additional use of mechanical techniques significantly enhances the effectiveness of thrombectomy but simultaneously provokes more embolism. Laser seems to negatively alter the structure of a thrombus and thus diminishes the effectiveness, while provoking embolism. All techniques had lowest effectiveness, but highest embolism with the mixed thrombus. This was particularly striking when a stent retriever was used with the mixed thrombus.

Effects of remote ischemic preconditioning (RIPC) and chronic remote ischemic preconditioning (cRIPC) on levels of plasma cytokines, cell surface characteristics of monocytes and in-vitro angiogenesis: a pilot study.

Remote ischemic preconditioning (RIPC) protects the heart against myocardial ischemia/reperfusion (I/R) injury and recent work also suggested chronic remote ischemic conditioning (cRIPC) for cardiovascular protection. Based on current knowledge that systemic immunomodulatory effects of RIPC and the anti-inflammatory capacity of monocytes might be involved in cardiovascular protection, the aim of our study was to evaluate whether RIPC/cRIPC blood plasma is able to induce in-vitro angiogenesis, identify responsible factors and evaluate the effects of RIPC/cRIPC on cell surface characteristics of circulating monocytes. Eleven healthy volunteers were subjected to RIPC/cRIPC using a blood pressure cuff inflated to > 200 mmHg for 3 × 5 min on the upper arm. Plasma and peripheral blood monocytes were isolated before RIPC (Control), after 1 × RIPC (RIPC) and at the end of 1 week of daily RIPC (cRIPC) treatment. Plasma concentrations of potentially pro-angiogenic humoral factors (CXCL5, Growth hormone, IGFBP3, IL-1α, IL-6, Angiopoietin 2, VEGF, PECAM-1, sTie-2, IL-8, MCSF) were measured using custom made multiplex ELISA systems. Tube formation assays for evaluation of in-vitro angiogenesis were performed with donor plasma, monocyte conditioned culture media as well as IL-1α, CXCL5 and Growth hormone. The presence of CD14, CD16, Tie-2 and CCR2 was analyzed on monocytes by flow cytometry. Employing in-vitro tube formation assays, several parameters of angiogenesis were significantly increased by cRIPC plasma (number of nodes, P < 0.05; number of master junctions, P < 0.05; number of segments, P < 0.05) but were not influenced by culture medium from RIPC/cRIPC treated monocytes. While RIPC/cRIPC treatment did not lead to significant changes of the median plasma concentrations of any of the selected potentially pro-angiogenic humoral factors, in-depth analysis of the individual subjects revealed differences in plasma levels of IL-1α, CXCL5 and Growth hormone after RIPC/cRIPC treatment in some of the volunteers. Nevertheless, the positive effects of RIPC/cRIPC plasma on in-vitro angiogenesis could not be mimicked by the addition of the respective humoral factors alone or in combination. While monocyte conditioned culture media did not affect in-vitro tube formation, flow cytometry analyses of circulating monocytes revealed a significant increase in the number of Tie-2 positive and a decrease of CCR2 positive monocytes after RIPC/cRIPC (Tie-2: cRIPC, P < 0.05; CCR2: RIPC P < 0.01). Cardiovascular protection may be mediated by RIPC and cRIPC via a regulation of plasma cytokines as well as changes in cell surface characteristics of monocytes (e.g. Tie-2). Our results suggest that a combination of humoral and cellular factors could be responsible for the RIPC/cRIPC mediated effects and that interindividual variations seem to play a considerable part in the RIPC/cRIPC associated mechanisms.

Effects of different ischemic preconditioning strategies on physiological and cellular mechanisms of intestinal ischemia/reperfusion injury: Implication from an isolated perfused rat small intestine model.

BACKGROUND: Intestinal ischemia/reperfusion (I/R)-injury often results in sepsis and organ failure and is of major importance in the clinic. A potential strategy to reduce I/R-injury is the application of ischemic preconditioning (IPC) during which repeated, brief episodes of I/R are applied. The aim of this study was to evaluate physiological and cellular effects of intestinal I/R-injury and to compare the influence of in-vivo IPC (iIPC) with ex-vivo IPC (eIPC), in which blood derived factors and nerval regulations are excluded. METHODS: Using an established perfused rat intestine model, effects of iIPC and eIPC on physiological as well as cellular mechanisms of I/R-injury (60 min hypoxia, 30 min reperfusion) were investigated. iIPC was applied by three reversible occlusions of the mesenteric artery in-vivo for 5 min followed by 5 min of reperfusion before isolating the small intestine, eIPC was induced by stopping the vascular perfusion ex-vivo 3 times for 5 min followed by 5 min of reperfusion after isolation of the intestine. Study groups (each N = 8-9 animals) were: iIPC, eIPC, I/R (iIPC group), I/R (eIPC group), iIPC+I/R, eIPC+I/R, no intervention/control (iIPC group), no intervention/control (eIPC group). Tissue morphology/damage, metabolic functions, fluid shifts and barrier permeability were evaluated. Cellular mechanisms were investigated using signaling arrays. RESULTS: I/R-injury decreased intestinal galactose uptake (iIPC group: p<0.001), increased vascular perfusion pressure (iIPC group: p<0.001; eIPC group: p<0.01) and attenuated venous flow (iIPC group: p<0.05) while lactate-to-pyruvate ratio (iIPC group, eIPC group: p<0.001), luminal flow (iIPC group: p<0.001; eIPC group: p<0.05), goblet cell ratio (iIPC group, eIPC group: p<0.001) and apoptosis (iIPC group, eIPC group: p<0.05) were all increased. Application of iIPC prior to I/R increased vascular galactose uptake (P<0.05) while eIPC had no significant impact on parameters of I/R-injury. On cellular level, I/R-injury resulted in a reduction of the phosphorylation of several MAPK signaling molecules. Application of iIPC prior to I/R increased phosphorylation of JNK2 and p38δ while eIPC enhanced CREB and GSK-3α/ß phosphorylation. CONCLUSION: Intestinal I/R-injury is associated with major physiological and cellular changes. However, the overall influence of the two different IPC strategies on the acute phase of intestinal I/R-injury is rather limited.

Sexual Dysfunction Before and after Treatment of Infrarenal Aortic Aneurysm Patients.

OBJECTIVE: Sexual dysfunction is supposed to be one major complication after treatment of infrarenal aortic aneurysms. It is still controversial how many patients suffer from a sexual dysfunction already before their operation and if there are any procedure-specific differences in postoperative sexual function depending on the operative procedure performed, for example, open (OAR) or endovascular aortic repair (EVAR). METHODS: To answer these questions we conducted this prospective unicentric study using the International Index of Erectile Function (IIEF) and analyzed the sexual function of 56 male patients with an infrarenal aortic aneurysm before as well as 3, 6, and 12 months after their operation. 23 patients (median age 66.5 years) were treated by OAR and 33 patients (median age 75.8 years) by EVAR. RESULTS: We observed that the majority of the 56 patients analyzed (91.3% of the 23 OAR patients and 96.8% of the 33 EVAR patients) suffered from a sexual dysfunction already before their operation. A 56.5% of the OAR patients and 67.7% of the EVAR patients even disclaimed a severe sexual dysfunction prior to surgery. Age and operation method showed no significant influence on the IIEF score (P= 0.647 and P= 0.621, respectively). The change of the IIEF score over the 4 time points also did not significantly differ for age and operation method (P= 0.713 and P= 0.624, respectively). The IIEF scores were significantly different between time points T1 and T4 (P= 0.042), whereas between the other time points no significant differences were found. CONCLUSIONS: Sexual dysfunction is very common in infrarenal aortic aneurysm patients even before their operation. OAR and EVAR do not cause a procedure-specific deterioration of the sexual function.

Strategies to Overcome the Barrier of Ischemic Microenvironment in Cell Therapy of Cardiovascular Disease.

The transplantation of various immune cell types are promising approaches for the treatment of ischemic cardiovascular disease including myocardial infarction (MI) and peripheral arterial disease (PAD). Major limitation of these so-called Advanced Therapy Medicinal Products (ATMPs) is the ischemic microenvironment affecting cell homeostasis and limiting the demanded effect of the transplanted cell products. Accordingly, different clinical and experimental strategies have been evolved to overcome these obstacles. Here, we give a short review of the different experimental and clinical strategies to solve these issues due to ischemic cardiovascular disease.

Is total arch replacement associated with an increased risk after acute type A dissection?

BACKGROUND: The surgical strategy for acute type A aortic dissection (AADA) usually consists of reconstruction of the tear-lesion in the affected part of the ascending aorta. The optimal strategy either to replace the ascending aorta (AAR) or to replace the ascending aorta and the total aortic arch (TAAR) is still under debate. Our study compares the 30-day mortality between AAR and TAAR in AADA surgery. METHODS: In this retrospective observational study, we analysed a total patient cohort of 339 patients who underwent surgery for AADA from January 2001 until December 2016. A propensity score-matched analysis between the AAR- and the TAAR-group with 43 patients for each subgroup was subsequently carried out. A multivariable analysis was performed to identify risk-factors for the 30-d-mortality. The 30-day mortality was defined as the primary end-point and long-term survival was the secondary endpoint. RESULTS: In 292 (86.1%) patients AAR and in 47 (13.9%) patients TAAR was performed for emergent AADA. Patients were older (P=0.049) in the AAR group. The median log Euro-SCORE was 25.5% (12.7; 41.7) for AAR and 19.7% (11.7; 32.2) for the TAAR patient cohort (P=0.12). Operative time, cardiopulmonary bypass- (CPB), cross-clamp- and ischemic time were significantly longer in the TAAR group (P<0.001). The overall 30-day mortality-rate was 17.7% (n=60) but was not significantly different between the two groups (P=0.27). Forty-nine (16.8%) patients died in the AAR and 11 patients (23.4%) in the TAAR group. After propensity-score matching, no difference in mortality was seen between the subgroups as well (P=0.44). Multivariable analysis identified the Euro-SCORE, long operation-time, postoperative dialysis and arrhythmia and administration of red blood cell concentrates as risk factors for 30-day mortality, but not for TAAR versus AAR. CONCLUSIONS: The therapeutic goal in AADA surgery should be the complete restoration of the aorta to avoid further long-term complications and re-operations. Though 30-day mortality and postoperative co-morbidity for AAR are comparable to those in TAAR after treatment of AADA in our analysis, decision-making for the surgical strategy should weigh the operative risk of TAAR against the long-term outcome.

Influence of moderate hypothermic circulatory arrest on outcome in patients undergoing elective replacement of thoracic aorta.

BACKGROUND: The ideal technique of cerebral protection in the surgical operation of the ascending aorta.is currently controversial. The current analysis evaluates the influence of moderate hypothermic circulatory arrest (MHCA) on elective replacement of the ascending aorta. METHODS: The study included 905 consecutive patients between 2001 and 2015, who underwent replacement of ascending aorta in MHCA. Patients were divided according to the postoperative 30-day mortality into survivor und non-survivor group. RESULTS: The average age was 66.5±11.1 in survivors vs. 70.0±10.5 years in non-survivors (P=0.057). The survivor group had a significantly lower Euro-SCORE II than non-survivors [4.0% (2.3, 6.6) vs. 9.5% (4.8, 20.9); P<0.001)]. The incidence of coronary heart disease (38.0% vs. 58.3%; P=0.022) and chronic renal failure (10.0% vs. 33.3%, P<0.001 was significantly higher in non-survivors. Intraoperatively, the cardiopulmonary bypass time [140 min (112, 185) vs. 194 min (164, 271); P<0.001] and cross-clamping time [91 min (64, 124) vs.119 min (94, 157); P<0.001] were significantly longer in non-survivors. However, the MHCA time was similar in both groups with statistical significance (P=0.023). Postoperatively, re-exploration due to bleeding was highly significant in non-survivors (5.4% vs. 33.3%; P<0.001) with a higher incidence of stroke (4.6% vs. 33.3%; P<0.001). The duration of mechanical ventilation was significantly shorter in survivors than in non-survivors [17 h (12, 26) vs. 147 h (49, 337); P<0.001] with a lower incidence of pulmonary infection (6.0% vs.16.7%; P=0.023). The multivariable logistic regression analysis showed age, female gender, aortic aneurysm, additional CABG, total arch replacement and cardiopulmonary bypass time were independent risk factors for 30-day mortality. CONCLUSIONS: The acceptable morbidity and mortality rates show that MHCA can be considered as a safe technique for cerebral protection in surgical replacement of thoracic aorta.

Hypoxia directed migration of human naïve monocytes is associated with an attenuation of cytokine release: indications for a key role of CCL26.

BACKGROUND: Numerous tissue-derived factors have been postulated to be involved in tissue migration of circulating monocytes. The aim of this study was to evaluate whether a defined hypoxic gradient can induce directed migration of naïve human monocytes and to identify responsible autocrine/paracrine factors. METHODS: Monocytes were isolated from peripheral blood mononuclear cells, transferred into chemotaxis chambers and subjected to a defined oxygen gradient with or without the addition of CCL26. Cell migration was recorded and secretome analyses were performed. RESULTS: Cell migration recordings revealed directed migration of monocytes towards the source of hypoxia. Analysis of the monocyte secretome demonstrated a reduced secretion of 70% (19/27) of the analyzed cytokines under hypoxic conditions. The most down-regulated factors were CCL26 (- 99%), CCL1 (- 95%), CX3CL1 (- 95%), CCL17 (- 85%) and XCL1 (- 83%). Administration of recombinant CCL26 abolished the hypoxia-induced directed migration of human monocytes, while the addition of CCL26 under normoxic conditions resulted in a repulsion of monocytes from the source of CCL26. CONCLUSIONS: Hypoxia induces directed migration of human monocytes in-vitro. Autocrine/paracrine released CCL26 is involved in the hypoxia-mediated monocyte migration and may represent a target molecule for the modulation of monocyte migration in-vivo.